Autonomic Nervous System PDF

Autonomic Nervous System Overview and Parasympathetic Nervous system Learning objectives • Know the structure of the autonomic nervous system, neurotransmitters and receptors • Know the processes of neurotransmission and transmitter termination • Understand how drugs can affect receptors associate...

Autonomic Nervous System Overview and Parasympathetic Nervous system Learning objectives • Know the structure of the autonomic nervous system, neurotransmitters and receptors • Know the processes of neurotransmission and transmitter termination • Understand how drugs can affect receptors associated with the autonomic nervous system • Understand how drugs can alter neurotransmission Learning objectives • Understand how drugs interacting with the ANS are used for clinical purposes • Understand how drugs can cause side effects and drug interactions Overview of the autonomic nervous system Processes that the autonomic nervous system regulates include: • Contraction/ relaxation of smooth muscle • All exocrine and some endocrine secretions • heart • intermediary metabolism Autonomic Nervous System • Sympathetic and parasympathetic systems have opposing actions in some physiological systems • Sympathetic nervous system activity increases in stress (fight or flight response) • Parasympathetic nervous system activity predominates during satiation and repose • see Rang et al, Pharmacology figure 13.1 Structure of the autonomic nervous system • Two neurons arranged in series • Comprising preganglionic and postganglionic cells • see Rang et al, Pharmacology figure 13.2 Sympathetic nervous system • Anatomically the sympathetic nervous system has a short preganglionic and long postganglionic neuron • Preganglionic neuron cell bodies lie in the lateral horn of the grey matter of thoracic and lumbar segments of the spinal cord • Then connect to the prevertebral chain of sympathetic ganglia which contains the cell bodies of postganglionic neurons Sympathetic nervous system • Many postganglionic sympathetic fibres reach peripheral destinations via branches of the spinal nerves • Sympathetic fibres destined for pelvic and abdominal sites have their cell bodies in prevertebral ganglia in the abdominal cavity • The exception to the two neuron arrangement is innervation of the adrenal medulla which releases catecholamines when stimulated and is considered to be a modified postganglionic sympathetic neuron Parasympathetic nervous system • Anatomically the parasympathetic nervous system has a long preganglionic and short postganglionic neuron • Preganglionic neurons exit the central nervous system through two discrete regions • The cranial outflow originates in the medullary region and innervates the eye, lacrimal and salivary glands and organs in the thoracic cavity Parasympathetic nervous system • The sacral outflow innervates pelvic and abdominal viscera via nerves called the nervi erigentes • Most postganglionic neurons are located in the target organ Transmitters in the autonomic nervous system • Principal transmitters are acetylcholine and noradrenaline • Preganglionic neurons are cholinergic releasing acetylcholine which acts on nicotinic ACh receptors • Postganglionic parasympathetic neurons release acetylcholine which acts on muscarinic receptors Transmitters in the autonomic nervous system • Postganglionic sympathetic fibres release noradrenaline which then acts on  and  adrenoceptors (an exception is the release of acetylcholine on muscarinic receptors in sympathetic neurons innervating sweat glands) Dale’s Principle • “A mature neurone releases the same transmitter (or transmitters) at all of its synapses” Acetylcholine receptors Nicotinic receptors are located in: • autonomic ganglia • neuromuscular junction • adrenal medulla • brain Nicotine receptors • Three main classes (CNS, muscle and ganglionic). • All are ligand gated ion channels with similar molecular structure but behave differently pharmacologically. • Nicotinic receptors are coupled to cation channels and mediate fast excitatory synaptic transmission. Figure 3.4 Nicotinic receptor subtypes • Pentameric structures • Five subunits that form the receptor-channel complex • Five types of subunits , , , ,  • Muscle receptor = (1)21 • Ganglionic = (3)2(2)3 • CNS = (4)2(2)3 • See Rang et al, Pharmacology Table 14.1 Muscarinic receptors • Are located in: smooth muscle • Cardiac muscle • Glands in the periphery • CNS • motor control • memory Amanita Muscaria Muscarine receptors • Gene cloning has identified 5 different types of muscarinic receptor, however only four have been distinguished functionally. • Muscarinic receptors are G-protein coupled receptors and can cause activation of phospholipase C, inhibition of adenylyl cyclase, activation of K+-channels or inhibition of Ca2+ channels • see Rang et al, Pharmacology Table 14.2 Synthesis and release of acetylcholine • • • Acetylcholine is synthesised within the nerve terminal from choline. Choline is taken up into the nerve terminal via a membrane transporter. The concentration of choline in plasma is 10M, but in close proximity to the nerve terminal where acetylcholine is broken down it is approximately 1 mM. Ach synthesis and release • Free choline is acetylated by the cytosolic enzyme choline acetyltransferase (CAT) which transfers an acetyl group from acetyl-CoA. • The rate limiting step is the availability of choline. Ach synthesis and release • • • Acetylcholine is then pumped from the cytosol via a transport protein and packaged into synaptic vesicles. Release occurs by exocytosis, triggered by calcium entry into the nerve terminal. Following its release ACh diffuses across the synaptic cleft to combine with receptors on the postsynaptic membranes Ach synthesis and release • • • Some of the released ACh will be hydrolysed by acetylcholinesterases bound to the basement membrane of the nerve terminal. ACh molecules bind to its receptors for approximately 2 ms then dissociates and is rapidly hydrolysed preventing it from binding another receptor see Rang et al, Pharmacology figure 14.2 Figure 14.2 Drugs affecting release of ACh • • • Increased release - 4-aminopyridine blocks potassium channels prolongs the action potential Inhibit synthesis – hemicholinium blocks the choline carrier Inhibit storage - red back spider venom disrupts synaptic vesicles and depletes nerve endings of ACh Drugs affecting release of ACh • Inhibit ACh release - botulinum toxin Anaerobic bacteria – Clostridium botulinum cleave proteins involved in exocytosis in nerve membrane progressive parasympathetic and motor paralysis – dry mouth, blurred vision, difficulty swallowing, respiratory paralysis toxipedia.org/display/toxipedia/Botulinum+Toxin Botox – Botulinum Toxin A • • • • Used for the treatment of muscle spasms IM or ID injections Causes flaccid paralysis of skeletal muscle Diminished activity of parasympathetic and sympathetic cholinergic nerves • Inhibition lasts from several weeks to 3-4 months • Immunoresistance may occur Drugs affecting release of ACh • • Compete with Ca2+ entry – Mg2+ ions, aminoglycosides Blocks active transport of ACh into vesicles vesamicol Drugs acting on ACh receptors 1. Muscarinic receptor agonists • Parasympathomimetic drugs • Key features of acetylcholine • Quaternary ammonium group (positive charge) • Ester group (partial negative charge) • For a diagram of the structure of ACh see Rang et al, Pharmacology Table 14.3 Effects of muscarinic receptor agonists Eye (M3/M5?) Contraction of: • Constrictor pupillae (pupil constriction) • Ciliary muscle (accommodation for near vision) Figure 14.5 Muscarine receptors Exocrine glands (M3) • Stimulation of exocrine glands with increases in sweating, lacrimation, salivation and bronchial secretions. M1 receptors stimulate HCl production Muscarine receptors Cardiovascular • Cardiac slowing (negative chronotropic effect, M2) • decreased cardiac output • reduced force of contraction (negative inotropic effect) • vasodilation (NO mediated effect, M3) Muscarine receptors Smooth Muscle (M3) Contraction of smooth muscle in: • Lung (bronchoconstriction) • Gastrointestinal tract (increased peristalsis) • Bladder (during micturition) Muscarine receptors Central effects (M1) • Tremor • Hypothermia • Increased locomotor activity • Improved cognition Bullock et al Fundamentals of pharmacology Fig 28.5 Clinical uses of muscarinic receptor agonists • • • Glaucoma Pupil constriction Bladder - Pilocarpine - Acetylcholine - Bethanechol Muscarinic agonist side effects • • • • • Generally poorly absorbed from GI tract Abdominal discomfort – vomiting, diarrhoea, intestinal cramps Bradycardia, hypotension, flushing Salivation, sweating Tremor, improved cognition Drug interactions and contraindications of muscarinic agonists • Other muscarinic agonists • Anticholinesterase medications • Ganglion blocking drugs Contraindications • Hypersensitivity, Parkinson’s disease, asthma, epilepsy, vagotonia, hypotension, severe bradycardia • Coronary artery disease • GI obstruction • Urinary obstruction • Hyperthyroidism • Peptic ulcer Drugs that enhance cholinergic transmission Inhibition of cholinesterases 1. Acetylcholinesterase • true cholinesterase • located in the basement membrane of the synaptic cleft • found in cholinergic nerve terminals and erythrocytes • demonstrates narrow substrate specificity (primarily acetylcholine) Drugs that enhance cholinergic transmission 2. Butyrylcholinesterases • otherwise known as pseudocholinesterase • found in the tissues of the liver, skin, brain and gastrointestinal smooth muscle • plasma • exerts broad substrate specificity (butyrylcholine, acetylcholine, procaine, suxamethonium, propanidid • genetic variants Acetylcholinesterases Serine hydrolases • 2 distinct regions • anionic site (glutamate residue) – binds choline moiety • esteratic site (histidine and serine) Anticholinesterases • Drugs that block the action of acetylcholinesterases and prevent the breakdown of acetylcholine. • see Rang et al, Pharmacology, table 14.8 Short acting • • • Edrophonium Quaternary ammonium compound that binds the anionic site of the enzyme Used to diagnose myasthenia gravis Medium duration • • Neostigmine (quaternary amine) Physostigmine (tertiary amines) Irreversible • • • • • • Pentavalent phosphorous compounds with labile group Referred to as organophosphates Insecticides - parathion Therapeutic uses – ecothiopate Chemical warfare – sarin Common drug for poisons and suicide https://www.youtube.com/watch?v=_jfGKbbZStw ORGANOPHOSPHATE INSECTICIDE ACTION Cholinesterase reactivation Pralidoxime • Brings an oxime group close to phosphorylated esteratic site • Attracts phosphate group from serine hydroxyl group • Must be used within few hours of contact with irreversible compound • Ageing occurs as organophosphate becomes irreversibly bound to site • Does not enter CNS Fig 14.8 Effects in autonomic cholinergic synapses • • • • • • • • Increased ACh at nerve terminals Increased secretions Increased peristaltic activity Bronchoconstriction Bradycardia and hypotension Pupillary constriction Fixation of accommodation for near vision Decreased intraocular pressure Clinical uses of anticholinesterases • Anaesthesia: Neostigmine reverses the effects of non-depolarising neuromuscular blocking drugs • Glaucoma: ecothiopate • Alzheimer’s disease: tacrine, donepezil, galantamine, rivastigmine • Myasthena gravis: neostigmine 2. Muscarinic receptor antagonists • • • • Parasympatholytic Antimuscarinic Anticholinergic Competitive antagonists Muscarinic receptor antagonists Composed of ester + basic gps Tertiary ammonium compounds • - actions in CNS • - Atropine • - Hyoscine Quaternary ammonium compounds • - no action in CNS • - ipratropium • - pirenzepine Effects of muscarinic receptor antagonists Exocrine secretions • Decreased secretions of salivary, lacrimal, bronchial and sweat glands Heart rate • Tachycardia Eye • pupil dilation (mydriasis) • paralysis of accommodation (cycloplegia) Effects of muscarinic receptor antagonists GI tract • Inhibition of gastrointestinal motility Smooth muscle • Relaxation of bronchial, biliary and urinary smooth muscle CNS • Antiemetic effects and treating motion sickness (hyoscine) • Reduce involuntary movements in Parkinson’s disease by inhibiting the extrapyramidal system • Reduced cognition/ arousal Bullock et al Fundamentals of pharmacology Fig 28.11 Clinical uses of muscarinic antagonists • • • • Sinus bradycardia Ophthalmic – dilate pupil Prevention of motion sickness Parkinsonism Clinical uses of muscarinic antagonists • • • Asthma Anaesthetic premedication Gastrointestinal endoscopy antispasmotic – irritable bowel syndrome, colonic diverticular disease peptic ulcer – reduce acid secretion via M1 receptors Contraindications • • • • • • Hypersensitivity Myasthenia gravis Severe cardiac disease GI obstructive disease Narrow-angle glaucoma Acute haemorrhage Contraindications • • • • • • Prostatic hypertrophy Urinary retention Pyloric obstruction Ulcerative colitis Toxaemia Febrile condition Ganglionic nicotinic receptor agonists • Dimethylphenylpiperazinium (DMPP) – no therapeutic value • Nicotine is provided in patches and gum for relief from cigarette smoking Bullock et al Fundamentals of pharmacology Fig 28.3 Ganglion-blocking drugs (nicotine receptor antagonists) • • interfere with ACh release prolonged depolarisation causing desensitisation • - nicotine nicotinic receptor antagonists • hexamethonium • clinically obsolete Bullock et al Fundamentals of pharmacology Fig 28.9